Abstract: Preliminary studies in rhesus macaques (RM) reveal that animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus rhadinovirus (RRV) develop B cell hyperplasia compared to RM infected with SIV alone. RRV, like Kaposi's sarcoma-associated herpesvirus (KSHV), encodes an interleukin-6 (IL-6) homologue, which is thought to be a necessary growth factor for Kaposi's sarcoma and the B cell-derived malignancy referred to as body cavity based lymphomas or primary effusion lymphoma in AIDS patients also infected with KSHV. The long-term objectives of this study aim to evaluate the role of the RRV vIL-6 homologue in viral-mediated B cell hyperplasia in the context of an SIV infection. Preliminary studies provided in the application strongly suggest that RRV vIL-6 is involved in RRV- associated disease, and as such provides an extremely value animal model to define the role of the viral encoded IL-6 in virus-mediated pathogenesis and to evaluate a novel therapeutic approach, utilizing a recombinant vIL-6-Fc fusion protein to induce anti-RRV vIL-6 responses to inhibit disease progression. To address this, the following Specific Aims are proposed: Specific Aim 1: Vaccination of immunocompetent and immunodeficient rhesus macaques with vIL-6-Fc fusion and define host immune response by enzyme-linked immunosorbent assays, neutralizing antibody responses, and cellular immune responses to vIL-6. Specific Aim 2 will define alternations in host response following RRV infection in vIL-6 vaccinated animals (immunocompetent and immunodeficient), utilizing the assays and procedures from Specific Aim 1 studies and the inclusion of studies with a recombinant RRV that encodes nonsense mutations in RRV ORF R2 (vIL-6). Finally, in Specific Aim 3 studies are proposed to evaluate the therapeutic potential of vIL-6 Fc fusion vaccination in animals infected with SIV and RRV. Parameters that will be measured include: viral load as defined by co-culture analysis and real time PCR; differential leukocyte counts in peripheral blood; serum protein electrophoresis for hypergammaglobulinemia; host and viral IL-6 by ELISA and bioassay; lymph node and bone marrow biopsies, and physical examination. Relevance: The incidence of KSHV infection and KSHV-associated disease in the developing and developed world will continue to grow as the population becomes immunodeficient due to HIV-1 infection or iatrogenic agents associated with organ transplantation. The results from the proposed studies utilizing the nonhuman primate animal model, should help elucidate the role of the vIL-6 in virus infection and disease, and provide new insights into the future development of therapies for KSHV-associated malignancies.